Critical role of TLR9 in acute graft-versus-host disease.
Graft-vs-host disease (GVHD) is a major complication after allogeneic bone marrow transplantation. Different studies have demonstrated that intestinal bacterial breakdown products and loss of gastrointestinal tract integrity, both induced by conditioning regiments, are critical in the pathogenesis of acute GVHD. Using C57BL/6 knockout mice, we evaluated the role of TLR4 and TLR9, which recognize bacterial LPS and DNA, respectively, in the GVHD associated with allogeneic bone marrow transplantation. When myeloablative-irradiated TLR9 knockout (TLR9(-/-)) mice were used as graft recipients, survival and clinical score of acute GVHD were improved as compared with the wild-type recipient mice (18/30 vs 1/31 mice still alive at day 70 in a total of four experiments); while no differences were observed using recipient TLR4 knockout (TLR4(-/-)) mice. The reduced mortality and morbidity in TLR9(-/-) mice related with reduced stimulatory activity of TLR9(-/-) spleen APCs after conditioning and reduced proliferation of allogeneic donor T cells. Experiments using TLR9(+/+) into TLR9(-/-) and TLR9(-/-) into TLR9(+/+) chimeric mice as recipients indicated a critical role for nonhematopoietic TLR9(+/+) cells interacting with bacterial breakdown products released in myeloablated mice. Altogether these data reveal a novel important role of TLR9 in GVHD, a finding that might provide tools to reduce this complication of allogeneic transplantation.
Calcaterra
Claudia
C
Molecular Biology Unit, Department of Experimental Oncology and Laboratories, National Cancer Institute, Foundation Istituto di Ricovero e Cura a Carattere Scientifico, Via Venezian, Milan, Italy.
Sfondrini
Lucia
L
Rossini
Anna
A
Sommariva
Michele
M
Rumio
Cristiano
C
Ménard
Sylvie
S
Balsari
Andrea
A
D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011828:Radiation Chimera / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D016019:Survival Analysis; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014184:Transplantation, Homologous
C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9